The prevalence of chronic rhinosinusitis (CRS) sharply increases after age 50 such that those age 60 years and above are twice as likely to have CRS than adults age 19-39 years. A large cohort study in the US also shows that the incidence of CRS with nasal polyps (NP; CRSwNP) between ages 65-74 is almost two-fold higher compared with CRS without NP or control. CRSwNP in the elderly has not been well investigated despite the disease burden for geriatric patients and its impact on other common geriatric problems. During the clinical management of CRS, antibiotics remain widely prescribed, repeatedly or chronically, resulting in widespread emergence of resistant, often deadly bacterial strains in the community. Commonly used antibiotics in CRS are also the main causes of Clostridium difficile colitis which can be fatal in the elderly. The treatment of NP with antibiotics, steroids, and even surgery is often unsatisfactory, leading to a diagnosis of recalcitrant CRSwNP. This recalcitrant CRSwNP is further associated with severe and uncontrolled asthma which is another health care issue of the elderly population because older asthmatic patients are more likely to be hospitalized than younger asthmatic patients and they have the highest death rate of any other age group. Therefore there is a pressing unmet need to better understand the pathogenesis of CRSwNP in the elderly so that we may develop a new and effective therapeutic approach to manage this challenging clinical problem. After joining the Northwestern sinus center, the principal investigator (PI) started investigating age-related differences in the pathogenesis of CRS supported by the T. Franklin Williams Geriatrics Faculty Development Award and has made several important discoveries. The PI found that elderly CRS patients had more severe disease and higher prevalence of NP and asthma compared with the non-elderly in our study population and there was a significant positive correlation between anti-dsDNA autoantibodies in NP tissue and age, suggesting increased local autoimmune inflammation in the elderly. The B cell activating factor of the TNF family (BAFF) is highly elevated in CRS patients, especially in NP. This elevation of BAFF was highly correlated with increased numbers of B cells/plasma cells, and high levels of local immunoglobulins. This was primarily found in patients who had had multiple sinus surgeries, suggesting that recalcitrant forms of disease may be characterized by an autoimmune etiology. This local autoimmune inflammation in CRSwNP may be linked to epithelial barrier dysfunction and consequential bacterial/fungal colonization because there was significant reduction of epithelial-derived antimicrobial peptides, S100A7 and S100A8/9, in CRSwNP. The PI found that S100A8/A9 was further reduced in the elderly and inversely correlated with aging, which indicates pronounced epithelial barrier dysfunction in the elderly. Therefore, the central hypotheses of this proposal are that; 1) activation and expansion of B cells and plasma cells by BAFF leads to a pronounced autoimmune inflammatory response and generation of NP in the elderly, and; 2) an age-related decline of epithelial innate immune function contributes to persistent inflammation in the elderly with CRSwNP. These hypotheses will be examined in three Specific Aims. Aim 1. To determine whether elderly CRS patients have more extensive and recalcitrant disease due to pronounced B cell/plasma cell activation and local autoimmune responses, we will recruit a cohort of control (18-49), mature adult (50-64), young old (65-74), and advanced old (>75) patients with CRSwNP undergoing their first surgery (n=15 each) and compare the presence of BAFF, B cell, plasma cells, local immunoglobulins, and local autoantibodies in NP at the time of surgery. We will prospectively follow their clinical courses and biomarkers. Aim 2. To assess whether BAFF is critical for the formation of NP and determine if this changes with age, we will examine the degree of inflammation, B cell activation, and local autoimmune response in a murine model of CRSwNP in adult (2 months old), middle aged (12 months old), and aged (18 months old) mice. We will also treat mice with a BAFF inhibitor before or after NP generation in this model of CRSwNP with different ages, and investigate the effects of the BAFF inhibitor on histopathologic responses, generation of B cells, plasma cells, IgA/IgG, and anti-dsDNA antibodies. Aim 3. To determine whether nasal epithelial cells from the elderly have an impaired ability to produce the host defense molecules S100 proteins in response to various stimuli, we will obtain and culture nasal epithelial cells from different age groups with CRSwNP or healthy controls (n=15 each), and compare the innate ability to produce S1008/9 with or without various stimuli. We will further investigate the cellula mechanism to test for a defect in generation of total/phosphorylated STAT3, a signaling factor that controls innate immune responses in epithelium, in the elderly. This proposal will advance our understanding of age-related differences in the pathogenesis of CRSwNP, and will identify new therapeutic targets for CRSwNP in the elderly. This award will also greatly assist the PI to obtain translational research capabilities as well as develop skills to establish a new mouse model of CRSwNP for discovering novel molecular targets that are most promising for CRSwNP in the elderly. In Aim 1, selecting and recruiting elderly patients with CRS and following them prospectively will greatly enhance my knowledge and skills in translational and clinical science for the elderly. In Aim 2, I will establish a new murine model of CRSwNP under the supervision of Dr. Kim. In Aim 3, I will obtain new skills in culturing primary nasal epithelial cells from humn subjects including air-liquid interface culture techniques. My long-term goal through this award is to become an experienced independent investigator in aging and immunology.